2-lower alkyl-4, 5-dihydro-3-pyridazinone-6-carboxamides and antitussive compositions



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3,069,318 Patented Dec. 18,1962

Z-LOWER ALKYL-4,5-DIHYDRO-3-PYRIDAZINONE- 6-CARBOXAMIDES AND ANTITUSSIVE COMPO- SITIONS Giulio Mafiii and Uberto Teotino, Milan, Italy, assignors to Lepetit S.p.A., Milan, Italy N Drawing. Filed July 22, 1959, Ser. No. 828,712 Claims priority, application Great Britain Dec. 5, 1958 Claims. (Cl. 167-55) The present invention relates to new antitussive agents. More particularly, the compounds with which the invention is concerned are represented by the following generic formula wherein R represents a lower alkyl group, R and R" are the same or different and represent hydrogen or lower alkyl groups.

The compounds of the invention, owing to their mechanism of action, are to be classified among the centrally acting antitussive agents, as has been shown by pharmacological tests. Moreover, they lack any narcotic action, thus proving in this respect superior to many natural or synthetic drugs currently employed in the management of cough.

The search for central acting, non-narcotic antitussive substances has been fairly intense in recent years, and has brought the use of some therapeutic agents, which are capable of increasing the threshold of the medullary cough center to afferent tussive impulses without the undesirable etfects of narcotics. It has now been found that the compounds of the present invention display an antitussive effect which is comparable with that of codeine and is free from the well known side effects of that generally employed drug.

The following table gives the average protecting dose, in mg./kg., of some of the compounds of the invention against cough caused by the inhalation of acrolein in the form of aerosol in guinea pigs.

Another peculiar property of the compounds of the invention is their extremely low acute and chronic toxicity, which allows their administration even in high and frequent doses. As far as the acute toxicity is concerned, the following comparative table is very illuminating, as it takes into account some drugs which are of widespread use for combatting cough.

LDEU, mg./kg. in mice suboral cutaneous 2Met5iyl-4,5-dihydro-3-pyridazinone-6-carbox- 1, 500 1, 500

ami e. 2-Methyl-3-pyridazinone ficarboxamide 1, 500 1, 500 2-1)?thyl-3-pyridazinone-ti carboxymethylam- 1, 2(10 1, 500

i e. 2-l \ethyl-3-pyridazinone-6-carboxydiethylam- 840 1, 220

1 e. 2-Butyl-4,fi-dihydro-B-pyridaZinone-fi-carbox- 1, 200 1, 500

amide. Codeine 370 250 Dextroznethorphan hydrooromide 275 N onaethyleneglycolrncthyl p-butylaminoben- 230 700 zoate.

Chronic toxicity of the compounds of the .invention is also of a very low order. Doses up to 300 mg./ kg. were administered daily to dogs for periods as long as 3 months, without observing any untoward efiects.

For therapeutical purposes, the compounds of the invention may be used as much or associated with a carrier, which may be a solid material, a sterile parenteral liquid or a syrup. When oral administration is selected as commonly used for this type of drugs, the therapeutic administration may be provided in the form of powders, capsules, tablets or other solid dosage forms. For parenteral use, liquid diluents may be employed, such as sterile distilled water in which some of the compounds are freely soluble. Although clinically appreciable efiects are observed with doses as low as 5-20 mg, the unit dosage is usually somewhat higher, and may safely reach 500 mg. and more when high dosages are required by particularly stubborn cases. For preparing the actual therapeutic compositions, the selected dose of any drug of the invention may be directly filled into capsules, either alone or associated with solid inert diluents and/or other active ingredients. Tablets may be prepared by mixing the selected drug with the commonly used tabletting materials, such as lactose, talc, cornstarch, stearic acid, magnesium stearate or the like. Ampoules are prepared by dissolving the selected drug in sterile distilled Water and filling the solution into ampoules containing a suflicient volume of liquid to provide the desired dosage of the drug. The

compositions may also advantageously take the form of a syrup, whereby the drug is dissolved in the common syrup in a concentration calculated to administer the proper dose, with or without the addition of suspending and/or flavoring agents and/or other drugs.

The process of preparing the compounds of the invention consists in reacting a 2-alkyl-3-pyridazinone-6-carboxylic acid chloride or alkyl ester of the formula wherein Z represents a vinylene or an ethylene: group and X represents a lower alkoxy group or chlorine, with an excess of ammonia or of a primary or secondary amine in a solvent. Although this procedure has given the most satisfying results in the majority of cases, it is intended that the preparation may be also carried starting from compounds in which the carbamyl group, either substituted or not, is already present in the position 6 of the pyridazine ring while the ring nitrogen of position 2 is unsubstituted. In this case the starting compound may be reacted with an alkyl halide or with another suitable alkylating agent to give the end compounds of the invention. Other obvious equivalents of the process of the invention are still possible; however, the yields of the process described here are highly satisfying, it is intended that all obvious modifications of the same fall within the scope of this application.

The following examples are illustrative of the invention.

Example 1 A mixture of g. 6-carboxy-4,5-dihydro-3-pyridazinone and 100 ml. of a 2% solution of hydrogen chloride in methanol is refluxed for 6 hours. On cooling, 6-carb0methoxy-4,5-dihydro-3 pyridazinone precipitates and is collected and dried. Yield 9 g. (85%), M.P. 136-137" C.

The carbethoxy analogue may be prepared by the same way using ethanol instead of methanol. Yield 85%, M.P. 135-136 C.

Ten grams of 6 carbomethoxy 4,5-dihydro-3-pyridazinone are dissolved in a sodium methoxide solution prepared from 1.5 g. sodium and 100 ml. methanol. At room temperature 10 g. methyl iodide are then added and the mixture is stirred at room temperature for 1 hour and at -60 for about 1 hour until the medium is no longer alkaline. Some disodium a-keto-glutarate formed as a by-product is filtered off and the filtrate is evaporated to dryness. The residue is extracted with chloroform. The chloroform is distilled off and the residue is recrystallized from methanol. Yield 6.5 g. M.P. -92" C. The product is 6-carbomethoxy-2-methyl-4,5-dihydro-3- pyridazinone. The above obtained compound (10 g.) is mixed with 25 m1. concentrated ammonia; the solid dissolves slowly, then a precipitate forms. After two hours at room temperature the product is collected and recrystallized from ethanol. Another crop is obtained after concentration of the mother liquor. Yield 6 g. (66%) of 6-carbamyl-2-methyl-4,5-dihydro-3-pyridazinone, M.P. -172 C.

Example 2 A mixture of 20 g. of methyl 2-butyl-4,5-dihydro-3- pyridazinone-6-carboxylate and 50 ml. of concentrated ammonia is allowed to stand for 1 hour. After this time the formed precipitate is collected and recrystallised 4 from ethanol. Yield 92% of 2-butyl-4,5-dihydro-3-pyridazinone-6-carb0xamide, M.P. 172174.

We claim: 1. A compound of the formula wherein R is a lower alkyl group and R and R are members of the class consisting 'of hydrogen and lower alkyl radicals.

2. 2-methyl-4,5-dihydro 3-pyridazinone-6carboxamide.

3. 2-butyl-4,5-dihydro-3-pyridazinone-6--carboxamide.

4. An antitussive composition in dosage unit form whose active ingredient consists essentially of from 0.05 to 0.5 gram of a compound of the formula References Cited in the file of this patent UNITED STATES PATENTS Leanza et al. Dec. 27, 1955 Kline Feb. 10, 1959 OTHER REFERENCES King et al.: J. Amer. Chem. Soc., vol. 74 (1952), pp'. 3222-4.

Gault' et a1.: Bull. Soc. Chim., France (1954), pp. 916-8.

Cucka et a1.: Chemical Abstracts, vol. 48 (1954), cols. 7975-6. 

1. A COMPOUND OF THE FORMULA
 4. AN ANTITUSSIVE COMPOSITION IN DOSAGE UNIT FORM WHOSE ACTIVE INGREDIENT CONSIST ESSENTIALLY OF FROM 0.05 TO 0.5 GRAM OF A COMPOUND OF THE FORMULA 